Good day, and thank you for standing by. Welcome to the AMT-130 Huntington's Disease Program Update. At this time, all participants are on a listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question during that session, you'll need to press star one one on your phone. Please be advised that today's conference is being recorded. I would now like to hand the conference over to Ms. Maria Cantor, Chief Corporate Affairs Officer. Ms. Cantor, please go ahead.
Good morning, and thank you for joining us. This morning, uniQure announced that it has postponed patient enrollment in the higher dose cohort of the phase 1/2 clinical trial of AMT-130 in Huntington's disease based on reported SUSAR events at this dose. We will discuss these events and provide an update on the program during this call. Joining me for the investor event and webcast are Matt Kapusta, our Chief Executive Officer, and Dr. Ricardo Dolmetsch, our President of Research and Development. We'll be making forward-looking statements during this investor call. All statements other than those of historical fact are forward-looking statements. They are based on management's beliefs and assumptions and on information available to management only as of the date of this conference call.
Our actual results could differ materially from those anticipated in these forward-looking statements for many reasons, including the factors described under the heading Risk Factors in uniQure's quarterly report on Form 10-Q, filed today, August 8, 2022, and other securities filings. Given these risks and uncertainties, investors should not place undue reliance on these forward-looking statements, and we assume no obligation to update these statements even if new information becomes available in the future. Now let me introduce Matt Kapusta, uniQure CEO.
Thank you, Maria, and good morning, everyone. On June 23, we announced encouraging 12-month follow-up data from the low-dose cohort of our U.S. phase 1/2 study that showed AMT-130 was generally well tolerated with neurofilament light levels near baseline in treated patients and meaningful lowering of mutant huntingtin protein supportive of target engagement. As announced in our press release this morning, in July, we were informed of two suspected unexpected serious adverse reactions, or SUSARs, in the higher-dose cohort of our open-label phase 1b/2 clinical trial of AMT-130 in Europe. Both of these patients, which were the first 2 patients dosed at a single clinical site, presented with localized inflammatory responses and other related symptoms within 1-2 weeks after their procedures.
A third patient who had previously been treated with a higher dose of AMT-130 in the U.S. in March of this year experienced severe headache and other related symptoms also shortly after their procedure. That event was initially deemed by the investigator as not related to AMT-130, but related to the procedure. Upon further review and discussion with the clinical trial's independent Data Safety Monitoring Board or DSMB, we have reclassified and reported that patient's reaction as a SUSAR. Importantly, these three patients are no longer hospitalized and have since fully or substantially recovered. The DSMB does not view these events as a dose-limiting toxicity, and thus far in our investigation, we have not yet identified the root cause of these events.
Nevertheless, we and the DSMB believe it is prudent to voluntarily and temporarily delay the enrollment and dosing of additional patients with the higher dose until we complete a comprehensive safety review in conjunction with our DSMB. During that time, we will continue our investigation and consider potential risk mitigation plans. We expect to do this over the next 60-90 days. This delay does not apply to any future procedures at the low dose, where no significant adverse events related to AMT-130 have been reported. Thus far, a total of 36 patients have been enrolled across our U.S. and European clinical trials, including 26 patients treated with AMT-130 and 10 control patients. Of those treated, 14 patients have received the higher dose, with some having now been followed for up to one year.
An additional 12 patients have received the lower dose, with some having now been followed for up to two years. Over the course of our studies, the independent DSMB has conducted six separate safety reviews, and aside from these three events, no other SUSARs have been reported. We do not expect this delay will have any impact on the data readouts in 2023. In the U.S. phase 1/2 study, all 26 patients in the first two dose cohorts have been enrolled, and the company continues to expect to present 1-2-year follow-up data in the Q2 of 2023. In the European phase 1b/2 study, the 6-patient lower dose cohort is fully enrolled, and the company continues to expect to present 1-year follow-up data in 2023.
Four of nine patients in the European study have been enrolled in the higher dose cohort. Before I hand the call over to Ricardo, I want to stress that patient safety and well-being will always be uniQure's top priority, and we are committed to working with the DSMB to complete our investigation as soon as possible. Now let me turn the call over to Ricardo.
Thanks, Matt, and good morning.
In mid-July, uniQure notified the health authorities of serious unexpected suspected adverse events related to two subjects in Europe treated with the higher dose of AMT-130 at a single clinical site.
The first patient experienced onset of motor and other striatal symptoms within 12 days after the procedure. Following admission to the hospital, an MRI was performed to show an enhanced T2-weighted MRI signal along the tract of the infusion and in the striatum and caudate, consistent with edema or swelling of the brain. Treatment with steroids was initiated and tapered to a final dose 10 days later. The subject is now fully oriented and has a normal neurologic exam, but still has subtle deficits in verbal fluency, memory, and attention relative to his preoperative state. The second patient experienced vomiting and raised intracranial pressure that presented 12 days after the procedure. Following admission to the hospital, the patient was found to have papilledema or
Ricardo.
Yes.
Ricardo. Excuse me. I'm sorry. If you don't mind going back in your remarks just a little bit because we were losing you on the audio just a little bit. You were fading out. I apologize interrupting you, but if you can go back-
That's fine.
A little bit to reiterate and just for real clarity. Thank you.
Absolutely. I apologize. Let me start again. In mid-July, uniQure notified the health authorities of serious unexpected suspected adverse events related to two subjects in Europe treated with a higher dose of AMT-130 at a single clinical site. The first patient experienced onset of motor and other striatal symptoms within 12 days after the procedure. Following admission to the hospital, an MRI was performed that showed an enhanced T2-weighted MRI signal along the tract of the infusion and in the striatum and in the caudate, consistent with edema or swelling in the brain. Treatment with steroids was initiated and tapered to a final dose 10 days later. The subject is now fully oriented and has a normal neurologic exam but still has subtle deficits in verbal fluency, memory, and attention relative to his preoperative state.
The second patient experienced vomiting and raised intracranial pressure that presented 12 days after the procedure. Following admission to the hospital, the patient was found to have papilledema or optic disc swelling, but the MRI did not show any evidence of edema in the striatum or along the tract of infusion. A lumbar puncture to remove 20 cubic centimeters of cerebrospinal fluid.
Ricardo.
And the-
Ricardo.
Subject fully resolved. Yes.
Yeah, I'm sorry. You were cutting out again. I just feel for the benefit of all of those listening in to the call, the content of what you're sharing is so important that it may be better to have Matt provide your remarks, and then we'll go to you, in the Q&A session. Again, I think that.
That's fine.
That's better for everyone listening in. Thank you. We'll have Matt pick up from.
Okay. Yeah, I apologize everybody.
All right, let me start off with the second patient experienced vomiting and raised intracranial pressure around 12 days after the procedure. Following admission to the hospital, the patient was found to have papilledema or optic disc swelling, but the MRI did not show any evidence of edema in the striatum or along the tracts. A lumbar puncture to remove 20 cc's of cerebrospinal fluid was performed, and the symptoms fully resolved, leading to discharge. The subject also received prophylactic antibiotics. A subsequent review of the safety data from the previous treated patients identified a third patient who received a higher dose of AMT-130 in March of this year at a U.S. site. This patient had a serious adverse event that was initially deemed by the investigator to be related to the procedure and not AMT-130.
The patient was admitted to the hospital seven days after the procedure with severe headache and vomiting. The patient was treated with analgesics and discharged from the hospital, but returned to the hospital 2 days later with a recurring headache, this time attributed to a CSF leak from a diagnostic lumbar puncture conducted at the prior visit. The patient was treated with a blood patch, which is a procedure by which blood is injected into the spinal canal to patch a hole through which cerebrospinal fluid is leaking. The patient was then discharged from the hospital and is now fully recovered. While a CAT scan taken on day seven did not reveal any abnormalities, an MRI taken on the patient's 14-day follow-up visit showed some edema or swelling in the striatum and the infusion tracts, which largely resolved by the patient's 30-day follow-up visit.
Upon discussion with the DSMB following the events observed in the European study, we have reclassified and reported this patient's event as a SUSAR and reported it to the authorities in late July. In compliance with our study protocols, uniQure has reported these events to the appropriate regulatory agencies, reviewed them in detail with our DSMB, and initiated a comprehensive investigation. While our investigation is not yet complete, we have thus far found no evidence that these events are related to quality of the clinical lots of AMT-130 or the shipping and handling of the drug. Nor have we found any evidence that they were related to anomalies in pharmaceutical preparation or the surgical procedures. As part of our investigation, we are also evaluating if there's any evidence that medical history or genetic predisposition may make some patients more susceptible to acute inflammation.
We will share the results of our investigations in a timely manner with regulators and with the medical and scientific community when possible. As all three events occurred within the first one to two weeks after the procedure, we believe that enhanced patient monitoring during this period has the potential to satisfactorily address any patient risk. We have developed additional risk mitigation protocols, including closer patient monitoring procedures and treatments, which we are currently discussing with our DSMB. The DSMB does not view these events as a dose-limiting toxicity. However, we and our DSMB believe it's prudent to temporarily pause additional patient dosing with the higher dose until we complete our safety review and investigation and have put the observation and risk mitigation plans in place. We expect this will occur sometime in early Q4 .
It's important to note that the delay does not apply to any future administration of the low dose of AMT-130. Thus far, no significant adverse events related to AMT-130 have been reported by any of the 12 patients treated with the lower dose, who have now been followed up for up to two years. The DSMB has allowed us to continue enrolling at the lower dose of AMT-130 for patients crossing over from the placebo group in the US study, which is expected to take place in the Q3 . We're optimistic this matter can be resolved in a timely manner and dosing of the 5 remaining patients in the European higher dose cohort to be resumed. I want to reiterate, we do not expect that this will have any impact on previously guided data readouts in 2023.
With 36 patients enrolled to date across both clinical trials, we expect to have sufficient data to maintain our timelines for regulatory discussions and decisions regarding potential registrational pathway. We also continue to be very encouraged by the 12-month update we provided in June on the patients in the lower dose cohort of the US study. These data show neurofilament light chain levels near baseline and lowering mutant huntingtin protein levels suggestive of meaningful target engagement. We believe this dose has the potential to provide benefits to patients suffering from Huntington's disease, and we look forward to working with the HD community to develop a treatment for this devastating disease. Now I'd like to open up the call for analyst questions, operator. Thank you.
Thank you, sir. As a reminder, to ask a question, you'll need to press star one one on your phone. We ask that you please limit yourself to one question and one follow-up, and please stand by as we compile the Q&A roster. One moment. Our first question will come from Paul Matteis of Stifel. Sir, your line is open.
Hey, this is Alex on for Paul. Thanks for taking our question. I just wanted to ask, have you shared these updates with the FDA yet? What has your dialogue been? Is there any risk to be placed in a clinical hold? Thanks.
Sure. This is Ricardo. Can you hear me?
Yep.
Yes.
Okay, good. Absolutely. Right after we got these reports from the sites, we shared them with both the EMA and the FDA, and so far we have heard nothing. We have not, at least at the moment, been put on any kind of clinical hold that we are aware of.
Hey, Ricardo. Yeah, I think your audio is still muffled, but just to repeat it, all of these events have been shared with the appropriate regulatory agencies in accordance with our protocols and regulations. You know, we have not had any specific dialogue with them or outreach that we received.
All right. Thank you.
Thank you. One moment, please, for our next question. Our next question will come from Joseph Schwartz of SVB Securities. Your line is open.
Hi, this is Beth on for Joe. Thanks for taking our question. I know you said that no clear root cause of these serious adverse events has been identified yet, but just curious what your initial hypothesis is on what could be driving it? Is there any sort of reason to believe that it could be associated with the degree of wild type huntingtin protein knockdown? Just since the serious adverse events occurred so closely to the administration period, curious if that could be playing any sort of role as well?
Yeah, I think that, obviously we need to complete our investigation before we weigh in specifically on a hypothesis. I will say that the proximity of these events, which have happened, you know, within days of the procedure, lead us to believe that it's probably unlikely that it's mechanism of action related. That it is, you know, probably something related to either, you know, an immune response or an inflammation associated with the product, or the procedure itself.
Got it. Thank you. I guess just as a quick follow-up, for the three patients who experienced these serious adverse events, how are they doing now? Just in terms of their NFL signal, have you been monitoring that and noticed any sort of differences in how it's, maybe the time it takes to return to baseline compared to others?
Yeah. The three patients are no longer hospitalized. Two of the three patients have fully recovered. One of the patients has substantially recovered. I think there's some subtle deficits that are continuing to be monitored. We have been doing the battery of follow-up tests, including neurofilament light. All of that information is going to be shared or is being shared with the Data Safety Monitoring Board, will be part of the comprehensive investigation.
Great. Thank you.
Thank you. One moment please for our next question. Our next question will come from Debjit Chattopadhyay of Guggenheim Partners. Your line is open.
Hey, good morning. Just a couple of clarifications. What was the volume of administration between the low and the high dose? Is there any difference in the rate of infusion between the two doses?
The volume, I think, is roughly the same. I think it's just the concentration that is different. I don't know, Ricardo, if you have changed your audio, but I believe that's the case. The rate of infusion, I think is, you know, consistent with the low dose procedure as well.
Got it.
Debjit, can you hear me? Sorry.
Yeah, I can hear you, Ricardo.
If you can hear me. Yeah. The volume is exactly the same at the low dose and the high dose. It's basically a total of 3 mL in for both.
Got it.
The rate of infusion is exactly the same.
Did you measure neutralizing antibodies at baseline?
Yes. None of the patients have neutralizing antibodies.
Got it. Thank you so much.
Thank you. Again, one moment please, for our next question. Our next question will come from Joseph Thome of Cowen. Your line is open.
Hi there. Good morning, and thank you for taking my questions. It seems like the disease course or the response course was a little bit different in the European patients and in the US, and then that US patient had the CSF issue. Have you ruled out that this is potential physician or administration error versus something with AMT-130? And then, second, what do you expect to learn, I guess, between now and that Q4 safety review? Thank you.
Until we finish our investigation, it's probably difficult to rule anything out at this juncture. Having said that, there's been no specific evidence that we have found that's directly implicated the procedure or the way that the procedure has been done, and it's not clear if that's something that you will be able to identify. It is true that two of these particular SUSARs happened at one clinical site, and they were the first two procedures that were performed at that clinical site. We'll continue to investigate that. As I said, we know there's no evidence that supports that thesis right now.
Between now and the next Data Safety Monitoring Board meeting, we're going to complete our investigation associated with, you know, reviewing all different aspects and factors that could contribute to the root cause. We'll in addition have some further follow-up associated with the 14 patients in the high-dose cohort. I'll just remind everybody that we have treated 14 patients in the high-dose cohort. You know, 11 of those 14 patients have not reported any significant adverse events related to AMT-130 with follow-up up to one year. All of that information will be compiled and pulled together for the DSMB as part of the review that we expect to have next month.
Perfect. Thank you very much.
Thank you. One moment please for our next question. Our next question shall come from Salveen Richter of Goldman Sachs. Your line is open.
Hey, good morning. This is Elizabeth on for Salveen. Thanks for taking our questions. A few from us. Have any more procedures been performed at that same site in the EU where the first two procedures were performed? Do you intend to message to the three after the safety review in Q4? You know, what are kind of the exact evaluations that are going to be performed during the safety investigation? If you could give more color on some of the specific things you're gonna be looking at. Thank you.
Okay. The answer to your first question is no, there's been no additional procedures that have been performed, at that particular site, or any site for that matter. Just to make that clear. Second is that we will provide an update after we complete, our review with the Data Safety Monitoring Board. Third, as I mentioned, you know, there's various different factors and analyses that we'll be looking at. One is that we're gonna continue to complete, our investigation of the critical quality attributes of the product. As I said, there's nothing thus far that suggests that there's any CMC-related issues or critical quality attributes, but we wanna finalize that analysis. We will continue to review the pharmaceutical preparation and shipping and handling associated with the product. Again, there's no evidence that suggests that.
There's additional data that will be accrued on follow-up visits. Again, remember that we have 26 patients that have been treated thus far that are doing quarterly follow-up visits. In particular, in the high-dose cohort, you know, a number of those analyses are batched. We will aggregate that data and review that data with the DSMB, and we expect to do that over the course of the next 60 and 90 days.
Got it. Thank you.
Thank you. One moment for our next question. Our next question shall come from Eliana Merle of UBS. Your line is open.
Hi, this is Jasmine on for Eliana. Thanks for taking our question. As you're thinking about building out the pipeline, beyond hemophilia and Huntington's, how are you thinking about potential business development there?
The pipeline beyond Huntington's disease, I mean, we're always looking at business development. Business development is something that is going to be part of our strategy. I think what we're committed to is being disciplined about business development, and making sure that any transaction that we might consider is strategic and that we believe can drive value for our shareholders. Beyond that, it's not something that I can really comment on.
Okay, thanks.
Thank you. Okay. One moment for the next question. Our next question will come from Danielle Brill of Raymond James. Your line is open.
Hey, guys. This is Alex on for Danielle. Is there any way this could be related to the duration of the surgery? You know, we're just kinda curious if there's any way that this could be rectified by the planned shortened surgical procedure. A quick follow-up or separate question on the control crossover. Was it ever an option for the patients or for you as a company to provide the low versus high dose for the placebo crossover patients who chose to crossover?
Yeah. This question with respect to duration, again, our investigation isn't complete yet, but I'll just remind, I mean, we've done 26 procedures that have been generally consistent in terms of duration. You know, this is the first, you know, three SUSARs or events like this that we've seen. It's, you know, our thesis is that it's probably not related to the duration of the procedure, but it's something that we'll continue to look at. With respect to the crossover. Listen, it's difficult to enroll patients in a first-in-man study where they have the possibility of sham control unless they have the potential to cross over to treatment. I think that was always something that, I think was an option that was left open.
Of course, it became something that we had to, you know, establish safety. I think that, you know, now we can offer that the DSMB has evaluated the information and believes that that's something that we should provide to the patients that had that control.
Right. If I could follow up, though. In terms of the crossover, I understand they could cross over. In terms of was that always an option of that they could receive the high dose and now that's off the table, or was that going to be determined after the normal safety and efficacy data?
I don't think there was any specificity about exactly which dose they got. I think that was something that would be determined based on the information that the DSMB had at the current time. The bottom line is there is an option for crossover patients to get the high-dose cohort, but it will depend.
Gotcha. Thanks for the color.
Thank you. All right. One moment for our next question. Our next question shall come from Sami Corwin of William Blair. Your line is open.
Hi there. Thanks for taking my question. Based on the biomarker data from the low-dose cohort and now the, you know, two starts in the high-dose cohort, are you guys rethinking your development strategy for AMT-130 at all? Like, in particular, are you reevaluating, possibly expanding the low-dose cohort?
We have not made any decisions yet. It's a little too early for that. I think we wanna complete our investigation and have our review with the DSMB, and at that point in time, we'll be better informed to weigh in on, you know, how we might bring forward the product and how that might impact the dose that we move forward.
Okay. Are there any changes in the timeline for conducting the procedures with the new surgical procedure?
Well, we wanted to complete dosing of the higher dose cohort. That was something that we messaged in the June call. That was really what we're focused on. We're probably not gonna be moving forward with the third dose cohort until we complete the enrollment of these remaining five patients. We think, again, this is something, a decision that we'll be able to make in the next 60-90 days. We think any impact on the third dose cohort will be minimal. The other part that I'll mention is that, again, the third dose cohort, it's not really a dose cohort.
It's a surgical adaptive cohort where we're gonna be mostly focused on understanding the feasibility and safety of the procedure. We don't think that impact is gonna impact late-stage development in a material way at this juncture.
Great. Thanks.
Thank you. Again, one moment for our next question. Our next question will come from Robyn Karnauskas and Nicole Germino of Truist. Your line is open.
Hi, this is Alex on for Robyn. I just wanted to clarify, if the DSMB concludes that the SAEs observed were procedure-related, would this third dose cohort with a different procedure to qualify to establish a new procedure that might be better or would you need additional clinical trials? Would you apply that to the low dose cohort if you wanted to expand that trial and carry that forward?
Yeah, again, it's gonna be difficult to hypothesize or conjecture about what might happen. I would say again that it's probably unlikely that it's generic procedure-related. We haven't seen any significant adverse events related to AMT-130 or the procedure, you know, in the entire low-dose cohort of 12 patients. There's 11 of the 14 in the high-dose cohort where we haven't seen it as well. It might be something, you know, related to the specific procedure, right, of that particular patient, but I think it's unlikely that there's some generic issue with the procedure itself, given the safety track record that we have over the last two years.
Any learnings that we get from this, to the extent that they're applicable, across the board, they certainly will be applied for the benefit of all patients. That would include, you know, risk mitigation or closer patient monitoring procedures.
Okay. Thank you.
Thank you. One moment as we get our next question. Up next, we have Luca Issi of RBC Capital Markets. Your line is open.
Oh, great. Thanks so much for taking my question. I know this was discussed a little bit earlier, but can you just help us understand how adverse events are dichotomized as related to the procedure versus related to the actual drug? Is that a pretty clear cut, or is this more like a fine line that comes down to clinical judgment? Again, any color there will be great. In terms of resuming the dose, what are your options here that you're contemplating in order to resolve the issue of the high dose? In addition to more frequent monitoring, what are the other levers that you can pull? How are you thinking about potentially refining inclusion/exclusion criteria? Are you considering maybe putting all patients on steroids prophylactically? Any additional color there would be great. Thanks so much.
Yeah. Adverse events are really characterized by the investigator. You know, those events are documented, and the specific investigator that is managing that patient really weighs in and attributes that to either the procedure or the product or unrelated to the best of their ability. It's really a judgment call, you know, that is really clinician-directed. It's also something that we would review with our Data Safety Monitoring Board and take into consideration their evaluation and recommendations as well. Then just remind me of your second question.
Yeah. What are your options going forward here to kind of solve the issues? You obviously talked about more frequent monitoring, but I was wondering if there's any other components here that you're contemplating?
Yeah, no, it's really. I mean, just as a reminder, all of these really happened in the first 1-2 weeks, right? You know, these are things that we can check in with patients on a daily basis before they're discharged from the hospital. We can do, you know, specific evaluations to make sure that they are meeting certain standards for discharge. There's the possibility that we could do, if there's anything abnormal or unusual, we can do an additional MRI procedure. If there are any symptoms of edema or inflammation, we can much more rapidly bring them in for immunosuppression or steroid treatment.
That's really what it is that we're focused on, is if there's any reactions that happen quickly, we can identify those reactions and then get the patient treated. With that, we think we can substantially mitigate any risk to the patients.
Super helpful. Thanks so much.
Thank you. One moment, please, for our next question. Our next question will come from Kristen Kluska of Cantor Fitzgerald. Your line is open.
Hey, everyone. Good morning. Just to switch gears on hemophilia B, is there any color behind the decision that the review couldn't be done in Europe on an accelerated basis? When in the U.S. and Europe do you and CSL Behring expect approval decisions to take place at this time? Can you remind us of the near-term milestone payments you are eligible for? Thank you.
Yeah, sure. With respect to the interactions with EMA, that is being handled completely by CSL. What we have heard from CSL is that there was no specific issue that was identified in the review that led to the switching from accelerated to standard review, that this was simply just a bandwidth issue, and you know, for EMA, and as a result that they needed some additional time for the review, but there was nothing specific. With respect to the timing of approval, I think that again is something that CSL will have to provide. I think what we've said is that we would now expect approval probably early next year, early in the Q1 of next year. That's based on the standard review. That's what we would.
With respect to milestones, we have stated that there's $175 million that would be received upon commercial launch of the product in the United States and Europe. There are additional milestones that are commercial related to certain net sales thresholds, as well as of the product in the United States and Europe. There are additional milestones that are commercial related to certain net sales thresholds, as well as commercial launch in Japan.
Thank you.
Thank you. One moment for our next question. Our next question will come from Judah Frommer of Credit Suisse. Your line is open.
Yeah. Hi, thanks for taking the question. First, maybe just following up on kind of the hypothesis that CMC or quality control in handling of products could have potentially been an issue here. Would those have been the same for the EU and the US product? Would those have come from the same batch or potentially been handled the same way despite being conducted at different sites?
Yeah. That's precisely the analysis that we do, right? That is, we just look to see if there's any lot-to-lot differences in any of the critical quality attributes. You know, based on that assessment, we do not believe that this is likely to be anything related to CMC.
Okay. Then just, you know, if we did end up in a situation where, you know, there was a dose limiting toxicity here, kinda can you assess kind of how that would affect your confidence in the program if you were maybe only going forward with the low dose? Maybe just remind us of your pre-clinical work and how the low dose could potentially confer functional benefit if, you know, we are gonna be in a functional study at some point, ideally with at least the low dose.
Yeah. This doesn't impact my confidence in the program, honestly. I mean, the purpose of a dose-finding study is exactly that, to find the right dose. We are really pleased with the data that we presented thus far from the first 10 patients in the U.S. study. We haven't seen any significant adverse events related to the low dose. We saw suppression of mutant protein in the cerebrospinal fluid that quite frankly was more meaningful than what we saw in the pre-clinical work. You know, that was over 50% suppression of mutant protein at 12 months. We've seen neurofilament light levels near baseline. You know, we're really encouraged by that data.
Even if there is a dose-limiting toxicity, you know, we're, you know, we'll have to obviously continue to follow patients that have received the low dose cohort, but we continue to be really pleased and encouraged about that dose.
Thanks.
Thank you. Again, one moment for our next question. Our next question shall come from Yanan Zhu of Wells Fargo. Your line is open.
Hi. Thanks for taking our questions. I think in 2021, FDA kind of convened an advisory committee meeting reviewing AAV gene therapy safety, and one of the topics was MRI abnormalities arising in patients who received intraparenchymal injections of AAV. I'm wondering, you know, based on those, the information presented there, how do you feel the cases you have been seeing similar or different from those cases, for example, in terms of timing of onset and whether patients are symptomatic or not? Thank you.
Yeah. It's hard for me to compare it against what was presented at the panel, but you know, as I say, you know, these are pretty acute cases. All the patients have been treated, have either fully recovered or substantially recovered. The most important thing is obviously the you know, the clinical prognosis for these patients. We're still learning a lot around what we're actually seeing in the MRI. What is this related to? In some cases, it's just the drug working, and it's not a bad thing. What is a bad thing, obviously, if there's any safety implications for the patients. The most important thing is that these patients can be treated, they can be monitored more closely, and that they can recover, right?
That's really the most important thing that we're focused on, and so we're pleased in that regard.
Got it. If I may have a quick follow-up. In the low dose patients, have any of them been followed up with MRI and whether there are any MRI findings in those patients? Of course, those will be non-symptomatic.
Yeah. All of them, every single patient is followed up with an MRI. Those MRIs happen, I believe, quarterly. I think what we reported at the time that we presented this data on the low dose cohort patient is that there were no structural abnormalities on the MRI. A full safety update will be provided when we present comprehensive data next year.
Got it. Thank you very much.
Thank you. One moment for our next question. Our next question will come from Yun Zhong of BTIG. Your line is open.
Hi, thank you very much for taking the question. This is a follow-up question on the low dose. Given the data, like you said, Matt, exceeded your expectations. I wonder how much effort and time would you like to spend to figure out the high dose before deciding maybe low dose is the optimal dose to move forward? Thank you.
Yeah, I mean, you know, I'll remind everybody. We have 14 patients that have received treatment with the high dose. There's remaining five patients in the European study that have not been treated thus far. This is in the first two dose cohorts. I mean, we can follow the 14 patients that we've treated and have very robust data to, I think, evaluate the high dose and the low dose next year. I'm not terribly concerned that we'll be spending a lot of energy or a lot of time evaluating this. I think to the extent that the DSMB continues to have pause when we do our safety review, we always have the possibility of contemplating treating those remaining patients with a low dose.
As I said, we'll cross that bridge when we have that discussion and provide an update after that time.
Thank you. One moment please for the next question. We have a follow-up question from Debjit of Guggenheim Partners. Your line is open.
Hey, thanks for that. A clarification. Is the EU segment enrolling subjects with similar disease stage and correct putamen volume as the United States?
Yes.
Got it. Do you have a sense where the NfL lines up in these patients? I know it's early, but given the U.S. patient who had a SAE back in March, do you have a sense of where NfL lines up in these patients with SAEs versus those who have not experienced an SAE?
Yeah, well, what I'll say is that, you know, we're not providing any of that specific details, but the information is being reviewed by the Data Safety Monitoring Board.
Got it. Thank you.
Thank you. One moment, please. We have a follow-up from Luca Issi of RBC Capital Markets. Your line is open.
Oh, great. I'll be quick. Just circling back on the hemophilia B delay in Europe. Is this related to the companion diagnostic, or how should we think about that? Thanks so much.
No, I answered that before. There's, you know, there's no specific issue that was cited by the European authorities related to this at all. This is not like there's a specific issue that they've identified and feel they need more time to review that specific issue. It's just a bandwidth issue with the agency that they feel they just need more time to complete the review.
Thanks so much.
Thank you. I'm seeing no further questions in the queue. I would now like to turn the conference back to Matt Kapusta for closing remarks.
Thank you, operator. In summary, we remain confident in the potential of AMT-130 in Huntington's disease, continue to be very encouraged by the data we recently presented. We hope to resume higher dose enrollment with minimal delay and do not expect any impact to the previously guided data readouts for next year. As mentioned earlier, patient safety will always be our top priority, and I'd like to express my gratitude to the patients, their families, and physicians who have been part of our clinical trial to date for their trust in us and their dedication to pursuing new treatment options. Thank you for attending this call. We look forward to providing further updates as soon as possible. Thank you.
Thank you. This concludes today's conference call. Thank you all for participating. You may now disconnect and have a pleasant day.